The developing nervous system is vulnerable to adverse effects due to exposures to a variety of substances in the environment, particularly metals and pesticides. At the same time, chronic exposure to low levels of neurotoxicants throughout life can lead to impaired neurologic functioning later in life, particularly in the elderly. As life expectancy increases, and the baby-boom generation approaches retirement age, neurodegenerative diseases such as IPD, Essential Tremor and Alzheimer's Disease will have a significant impact on quality of life, and will represent significant financial costs to the health care system. Collectively, the investigators in this research core are interested in understanding the extent to which, and mechanisms 295 whereby, populations exposed to known quantities of neurotoxicants suffer adverse consequences on the nervous system. The populations under investigation, which include birth cohorts in Yugoslavia and northern Manhattan, populations of adults and children chronically exposed to arsenic in drinking water in Bangladesh, and populations of the elderly in northern Manhattan, represent groups of individuals who have been remarkably well characterized for a variety of chemical exposures and other risk factors for adverse neurologic outcomes. At the same time, laboratory based scientists are exploring the mechanisms whereby the compounds of interest alter normal function. The overall goals of the Neurotoxicology/Neurodegenerative Disease Research Core are: I) to promote and facilitate interdisciplinary neuroscience-related research that will define the magnitude of effect of exposure to substances in the environment that are believed to be involved in the etiology of neurologic disease. These substances include metals (Pb, Mn, Fe and As), pesticides (chlorpyrifos, diazinon, propoxur, and others), 13- carboline alkaloids (harmane and harmine), and other factors; and 2) to unravel the cellular and molecular mechanisms whereby these substances exert their effects. The core is responsible for furthering the development of existing and new investigations of environmental exposures that affect the incidence and/or progression of diseases of the central and peripheral nervous systems. The Specific Aims currently under investigation include: 1) to define the cellular and molecular events involved in chemical models of Parkinsonism and in IPD, with the goal of defining those that are common to each; 2) to elucidate the environmental risk factors associated with the onset of IPD, Essential Tremor, and Alzheimer's Disease; 3) to examine, in both humans and animal models, the relationship between environmental Pb exposure and brain function, with particular interest in the possible mediating effects of Pb on thyroid hormone fate and transport; 4) to determine whether exposure to arsenic in drinking water is associated with adverse neuropsychologic effects in children, and polyneuropathy in adults; and 5) to develop biomarkers of prenatal pesticide exposure in humans.